The study of cardiovascular homeostasis by means of spectral analysis of cardiovascular variability is becoming increasingly popular in human psychopharmacology to understand the often complex cardiovascular (side-) effects of psychoactive drugs. Quantification of spontaneous beat-to-beat variations in heart rate (HR) and blood pressure (BP) under standardized situations may provide indices of parasympathetic and sympathetic cardiovascular control (1-3). By means of spectral analyses, the cardiovascular fluctuations can be decomposed into three relevant frequency bands (low, mid, and high frequencies). The respiratory-related high-frequency fluctuations of HR (oscillations with a frequency ∼0.2-0.4 Hz) may reflect cardiac vagal (parasympathetic) modulation. Mid-frequency fluctuations (oscillations with a frequency ∼0.1 Hz) of BP may reflect baroreflex-mediated sympathetic control, whereas low-frequency cardiovascular fluctuations (oscillations <0.07 Hz) may be of variable origin (4-8). In addition, relations between SBP and IBI time series in the frequency domain can be computed, reflecting the arterial baroreflex control of HR (9,10).
In patients with a variety of cardiovascular disorders, treatment of accompanying anxiety symptoms with benzodiazepines is common practice. In these patients, in whom suppression of anxiety-induced autonomic nervous system activation may be desirable, it is relevant (a) to know the extent to which the central anxiolytic-sedative properties of benzodiazepines may induce an overall damping of autonomic nervous system activity, (b) to assess whether specific effects on the autonomic nervous system occur that are unrelated to sedation, and (c) to establish potential differences between benzodiazepines regarding these effects.
Benzodiazepines exert their action primarily by means of the γ-aminobutyric acid-a (GABAa)/benzodiazepine-receptor complex. GABAa/benzodiazepine-receptor agonists may affect sympathetic tone by suppression of corticotrophin-releasing hormone (CRH; 11,12). The role of peripheral benzodiazepine receptors in the vascular effects of benzodiazepines still remains elusive (13). Benzodiazepines can also affect cardiac vagal tone by means of GABAergic inhibitory mechanisms (14). Studies in humans support this observation: both diazepam and lorazepam can influence cardiac vagal modulation as quantified by means of spectral analysis of HR variability. However, the direction and magnitude of the effect may depend on dosage, pharmacokinetics, and experimental circumstances (15,16). The triazolobenzodiazepine alprazolam did not influence cardiac vagal tone after 6 weeks of medication in patients with generalized anxiety disorder (17). Alprazolam has been found to suppress sympathoneural and adrenomedullary activity (reduced BP; reduced plasma concentrations of adrenaline and noradrenaline), although conflicting data do exist (e.g., 18-23). No quantitative data are available on the beat-to-beat analysis of both HR and BP fluctuations by means of spectral techniques after alprazolam administration.
We recently reported the short-term effects of 1 mg alprazolam and 2 mg lorazepam orally on catecholaminergic and cardiovascular activity during supine rest, mental load, and orthostatic challenge in healthy volunteers (21). These dose levels of the two benzodiazepines are considered to be clinically equivalent. During supine rest, alprazolam, but not lorazepam, reduced mean BP, whereas HR slightly increased after lorazepam but not after alprazolam administration. These cardiovascular effects during supine rest were accompanied by a small reduction in plasma catecholamine concentrations after alprazolam administration. To gain insight into the differential effects of the two drugs on plasma catecholamines and hemodynamic parameters, we reanalyzed the cardiovascular data of this study by means of spectral analyses of beat-to-beat variations in interbeat interval (IBI) and systolic and diastolic blood pressures (SBP, DBP).
Electrodermal activity of the eccrine sweat glands was monitored by measuring the skin conductance level (SCL) of the nondominant hand. Innervation of the eccrine glands is primarily regulated by the sympathetic nervous system, although the postganglionic neurotransmitter is acetylcholine. Several studies have documented the attenuating properties of benzodiazepines on SCL (e.g., 24,25). We explored whether SCL after 1 mg oral alprazolam was different from that after 2 mg lorazepam, in comparison with placebo.
Subjects and procedures
Details of the subjects and procedures of this study have been presented elsewhere (21). In short, 12 healthy male volunteers (mean age, 22 years; SD, 2 years) received, in a randomized placebo-controlled double-blind crossover design, either an oral dose of 1 mg alprazolam, or 2 mg lorazepam, or a placebo, on three different days that were separated by ≥5 days. Each experimental session lasted from 8:15 a.m. to 12:15 p.m. Oral dose administration took place at 8.15 a.m.; 30 min there-after, the measurements started. All subjects were studied during three periods of supine rest (15 min each) with 60 min between the periods, during which several tests were performed (mental load, orthostatic challenge). Only data of the last 5 min of each supine rest period are presented here.
Measurements and analyses
Plasma concentrations of benzodiazepines. Blood sampling for assay of plasma concentrations of alprazolam and lorazepam occurred after each resting period, at 45 min, 2 h, and 3 h and 15 min after oral administration. Blood (10 ml) was collected in EDTA tubes, centrifuged (10 min, 4,000 g), and plasma was stored at −70°C until assay. Alprazolam and lorazepam plasma concentrations were assayed by means of high-performance liquid chromatography with UV detection, after isolation from plasma by an extraction with heptane:isoamylalcohol (90:10).
Plasma catecholamine concentrations. For determination of plasma adrenaline and noradrenaline concentrations, blood samples (10 ml in chilled heparinized tubes containing 12 mg glutathione) were obtained after each supine rest period. The blood samples were centrifuged at 4°C; plasma was subsequently frozen at −70°C until assay. Catecholamines were assayed by means of high-performance liquid chromatography with fluorimetric detection after isolation from plasma by a specific liquid-liquid extraction method and derivatization with the selective fluorogenic agent 1,2-diphenylethylenediamine (26).
Physiological signals. ECG, BP, and respiration were recorded continuously during the sessions on a multichannel FM-type analog recorder (Racal Store 14 DS, Sarasota, FL, U.S.A.). The ECG was derived by using a precordial lead, amplified by means of a polygraph (Nihon Kohden, Tokyo, Japan). Blood pressure was measured by using a servo-plethysmomanometer for continuous noninvasive measurement of finger arterial BP, by using the volume-clamp technique of Penaz (27,28; Finapres 2300 NIBP monitor; Ohmeda, Englewood, CO, U.S.A.). The cuffed middle finger of the nondominant hand was kept at the level of the heart to optimize the correspondence with intrabrachial pressure changes (29). Thoracic and abdominal respiration were measured by means of impedance plethysmographs (Nihon Kohden, Tokyo, Japan). Adhesive disposable Ag/AgCl electrodes were used for the thoracic and abdominal recordings, placed at the level of the nipples and the abdomen, respectively. Skin conductance level (SCL; Nihon Kohden, GSR-2100) was recorded by means of two active Ag/AgCl electrodes with an effective area of 0.5 cm2, attached to the medial phalanx of the index and ring fingers of the nondominant hand, by using Physio-Control Derma-Jel as intermediate.
Analyses of physiological signals. The signals were off-line digitized at a sample frequency of 1,000 Hz on a personal computer (Dell Optiplex GXL5166, Dell Computer Corporation, Austin, TX, U.S.A.) connected to an analog/digital converter (DI-200 PGH, Dataq Instruments, Inc., Akron, OH, U.S.A.). RR intervals (IBI) of the ECG were detected with an accuracy of 1 ms, and transposed to HR time series. SBP and DBP values were defined per RR interval of the ECG. Time series of IBI, SBP, and DBP were scrutinized for artifacts by means of visual inspection. Good-quality cardiovascular and SCL data were averaged per 5-min segments during the three subsequent 15-min periods of supine rest, which started at 30 min, 1 h and 45 min, and 3 h after oral drug administration.
Spectral analyses of cardiovascular signals. The 5-min segments of time series of HR, SBP, and DBP were subjected to a discrete Fourier transform based on nonequidistant sampling of the R-wave incidences (CARSPAN program; 30,31) to obtain power spectra of the rhythmic oscillations over a frequency range of 0.02-0.5 Hz, with a resolution of 0.01 Hz. For each time segment, the power was calculated for the low-frequency band (LFB, 0.02-0.06 Hz), the mid-frequency band (MFB, 0.07-0.14 Hz), and the high-frequency band (HFB, 0.15-0.50 Hz). Spectral energy was expressed in relative terms (i.e., as fraction of the mean value of the considered signal during a particular period (squared modulation index, to be compared with squared variation coefficient; 32). As an index of baroreflex sensitivity (BRS), per time segment, the gain (or modulus) in the MFB between the systolic pressure values and the RR-interval times was computed, based on those frequency points within the 0.07- to 0.14-Hz range with a coherence between the two signals of ≥0.35 (10).
Respiration. Per time segment, samples of the respiratory signal were obtained at each incidence of the R wave. Subsequently, these respiratory time series were subjected to spectral analyses (33). Power spectra of the respiratory time series were evaluated primarily to assess whether changes in cardiovascular variability due to benzodiazepine administration were related to changes in respiratory frequency. Per time segment, the dominant respiratory frequency in the power spectrum was assessed.
Data are presented as mean values and standard deviations (SD). A logarithmic transformation was applied to the SCL data and the cardiovascular spectral data because of skewness of the distributions. The data of the last 5 min of each 15-min period of supine rest were used for the statistical analyses. Statistical analyses were performed by using the SPSS for Windows Release 6.0. Two-factor multivariate analyses of variance (MANOVA) for repeated measurements were performed to explore the time-dependent effects of alprazolam and lorazepam on the autonomic parameters: factor DRUG (placebo, alprazolam, lorazepam) and factor TIME (30 min, 1 h 45 min, 3 h) as well as the interaction between factors DRUG and TIME were studied. In this explorative study, a p value of <0.05 was considered significant. When a significant main effect for factor DRUG was found, additional MANOVAs for pairwise comparisons of the drugs versus placebo were performed, always including factor TIME. For these pairwise comparisons, a p value of <0.025 (Bonferroni correction) was used to indicate a significant effect. The averaged tests of significance were used when Mauchly's test of sphericity revealed no deviations from the symmetry assumptions. The Huyn-Feldt epsilon was used to adjust the degrees of freedom for the averaged results.
Plasma concentrations of benzodiazepines
Plasma concentrations of alprazolam and lorazepam are depicted in Fig. 1 Concentrations of alprazolam and lorazepam increased only slightly during the sessions.
Plasma catecholamine concentrations
During the three sessions, plasma noradrenaline and adrenaline concentrations showed a time-dependent increase (Tables 1 and 2). Alprazolam significantly reduced plasma noradrenaline concentrations versus placebo (p = 0.01). The slight reduction of plasma adrenaline concentrations after alprazolam administration did not reach statistical significance (p > 0.05). Lorazepam had no effect on plasma catecholamine concentrations.
Interbeat interval and heart rate. During the three sessions, HR gradually declined, whereas IBI, variation co-efficient of IBI, and the low-, mid-, and high-frequency band fluctuations of HR showed a time-dependent increase (Tables 1 and 2; Fig. 2). After alprazolam administration, HR showed a stronger time-dependent decrease (from 64 to 57 beats/min) than after placebo (from 63 to 60 beats/min), whereas HR hardly changed after lorazepam administration (from 62 to 61 beats/min). After lorazepam administration, overall variability of IBI (variation coefficient) was significantly increased versus placebo (p < 0.02), whereas low-frequency band power was significantly increased versus placebo and alprazolam. Regarding high-frequency band power, we observed a time-dependent increase after alprazolam administration, whereas after lorazepam administration, the initial increase of high-frequency band power at 30 min (in comparison with placebo) did not change much during the subsequent part of the session.
Systolic blood pressure. Alprazolam and lorazepam did not affect SBP, the variation coefficient of SBP, or the power of the low frequency band (Tables 1 and 2). Regarding the power of the mid-frequency band of SBP, we found an increase at 30 min after administration of alprazolam and lorazepam and a decrease after 3 h, in comparison with placebo. On average, the effects were stronger for alprazolam. Alprazolam increased the high-frequency band power of SBP versus placebo (p < 0.01).
Diastolic blood pressure. DBP increased time-dependently during all conditions (Tables 1 and 2; Fig. 2). Alprazolam induced a small reduction of DBP (∼2-4 mm Hg vs. placebo), whereas DBP after lorazepam increased after 3 h of dose administration (∼4 mm Hg vs. placebo): the difference between the DBP levels of the alprazolam and lorazepam condition was significant (p < 0.01). Lorazepam increased the variation coefficient of DBP versus placebo (p < 0.02). Similarly, the power of the low-frequency band was significantly increased after lorazepam administration, in comparison with placebo (p < 0.01). Mid-frequency band power after alprazolam was increased versus placebo at 30 min after dose administration, but subsequently declined to levels below placebo at 1 h 45 min and at 3 h. Mid-frequency band power of DBP after lorazepam appeared, on average, higher at 30 min and reduced versus placebo at 3 h after dose administration. Both alprazolam and lorazepam increased the high-frequency band power of DBP versus placebo (alprazolam, p < 0.001; lorazepam, p < 0.01).
Baroreflex sensitivity. The index of baroreflex sensitivity showed a time-dependent increase during all conditions. Alprazolam showed a larger time-dependent increase at 1 h 45 min and at 3 h than did placebo or lorazepam, whereas in comparison to placebo, the BRS index after lorazepam already appeared increased at 30 min after dose administration (Table 2; Fig. 3).
Respiratory frequency. Alprazolam and lorazepam did not affect respiratory frequency (Tables 1 and 2).
Skin conductance level. SCL showed a significant time-dependent increase during the three conditions (Fig. 3; Table 2). After 1 mg alprazolam, SCL was significantly reduced versus placebo (p < 0.01). After 2 mg lorazepam, a mild reduction of SCL was observed versus placebo (p < 0.05).
Benzodiazepines and cardiovascular activity
In this study, noninvasive indices of sympathetic and parasympathetic regulation were used to analyze the cardiovascular effects of alprazolam and lorazepam.
After alprazolam, DBP was slightly reduced during supine rest. Reduced BP after alprazolam administration was reported before (e.g., 20,34,35). Vasomotor fluctuations of the mid-frequency band of SBP and DBP first showed an increase at 30 min and a subsequent decrease at 1 h 45 min and 3 h, indicating a time-dependent effect of alprazolam on noninvasive indices of sympathetic modulation (initial increase vs. subsequent decrease). Attenuation of cardiac sympathetic tone (at 1 h 45 min and 3 h) corresponded with our findings of reduced noradrenaline plasma levels in these subjects. The changes in mid-frequency BP fluctuations were not reflected in the corresponding HR fluctuations because, during supine rest, HR variations are primarily under parasympathetic control (e.g., 6). The gradual decrease of HR after alprazolam administration and its increasing effect on high-frequency band power of HR suggests a mild vagotomimetic effect of alprazolam. These effects were accompanied by a time-dependent increase in baroreflex sensitivity and were unrelated to changes in respiratory frequency. McLeod et al. (17) reported no effects on cardiac vagal tone in the sitting position after 6 weeks of treatment with alprazolam in patients with generalized anxiety disorder. Our data indicate that after short-term administration, alprazolam influences both sympathetic and cardiac vagal mechanisms in a time-dependent manner.
For lorazepam, we did not observe a reduction of HR and found a significant increase in low-frequency band fluctuations of HR and DBP, but no effects on overall SBP, DBP, or respiratory frequency. Normal or increased HR after oral lorazepam administration was reported before (36). In our previous study (16), we observed a dose-dependent reduction of HR and increase of HR variability after intravenous lorazepam (increasing dose level, 0.06-0.5 mg) during situations of rest after a stressful task, but no effects on BP variability. These findings emphasized that lorazepam can influence cardiac vagal tone, but the direction of the effect was probably related to rebound phenomena due to the strain of the stress tasks. Low-frequency band fluctuations in HR and BP have been found to be of variable origin (slow respiratory oscillations, renin-angiotensin system activity, thermoregulatory influences; 1,2,4). Furthermore, in this frequency range, a low coherence exists between HR and BP time series, indicating a dissociation between HR and BP fluctuations (37), making unequivocal interpretation difficult. The effects of lorazepam on midfrequency band fluctuations of BP, high-frequency band fluctuations of HR, or BRS index were less clear than for alprazolam. Regarding overall levels of BP and mid-frequency band fluctuations of BP, these findings corresponded with the absence of significant changes in plasma catecholamine levels after lorazepam. Our data therefore revealed only limited effects of 2 mg oral lorazepam on cardiovascular indices of sympathetic and parasympathetic tone during the first 4 h after administration.
High-frequency band fluctuations of BP are presumed to reflect non-neuronal processes, related to the mechanical thoracic coupling between respiration and the vasculature; the effects of respiration-induced fluctuations of HR appear to play only a minor role in the origin of these BP fluctuations (9,38). Both alprazolam and lorazepam increased high-frequency band fluctuations in DBP during the whole recording period; for alprazolam, this effect was also present in SBP. Both benzodiazepines did not affect respiratory frequency (21). This does not exclude changes in respiratory tidal volume, which we did not measure. It is presently unclear whether the increase in high-frequency band fluctuations of BP reflects nonspecific effects, influenced by the sedative and muscle-relaxing properties of benzodiazepines, which might have caused an increase in tidal volume and consequently related changes in intrathoracic pressure and venous return. An alternative explanation could be that benzodiazepines directly influence venous return via a venodilatory mechanism (13,38).
Benzodiazepines and skin conductance level
The reduction of SCL, particularly after alprazolam administration, is in agreement with findings of other benzodiazepine studies (24,25,39). The effect has been assumed to be related to the anxiolytic-sedative central properties of benzodiazepines: anxiolysis-sedation may reduce sympathetic arousal, which may result in the attenuation of SCL (e.g., 24). Also in this study, subjective sedation after alprazolam and lorazepam was equally and significantly increased (21). However, Geddes et al. (25) pointed out that the effect of benzodiazepines on SCL is not necessarily limited to the anxiolytic-sedative properties, because other sedation-inducing drugs such as propofol do not reduce SCL. The specific role of GABAergic neurotransmission in these processes needs to be further elucidated. In relation to this, it is noteworthy that increased sweating is one of the typical characteristics of the withdrawal syndrome as a result of physiological dependence on benzodiazepines (40).
Alprazolam versus lorazepam
Small, but significant, effects of alprazolam on sympathetic and parasympathetic processes were detected, whereas for lorazepam, these effects were less clear.
Multiple mechanisms are involved in controlling the short-term autonomic responses to benzodiazepine administration. Several anatomically and functionally distinct central GABAergic mechanisms have been found to contribute to cardiovascular homeostasis (41). Interaction of these mechanisms with locus coeruleus firing, neuroendocrine system activity (CRH; hypothalamic-pituitary-adrenal axis; sympathoadrenomedullary system), and behavioral changes (anxiolysis/sedation) complicates equivocal interpretation of the autonomic effects of benzodiazepines. The potential role of peripheral benzodiazepine receptors in these processes still needs to be elucidated (13).
In this study, serum concentrations of 1 mg alprazolam and 2 mg lorazepam were rather similar with respect to time course and absolute levels. However, it is difficult to estimate the activity of both compounds at the central benzodiazepine receptor due to differences between alprazolam and lorazepam in central potency and free-fraction values in serum (42). With this design, it was not possible to compare multiple doses of both compounds. However, we observed equivalent increases in subjective sedation after 1 mg alprazolam and 2 mg lorazepam (21). In view of these observations and the parallel time course of the plasma concentration curves, it seems that the differences observed in this study cannot simply be ascribed to differences in potency of 1 mg alprazolam and 2 mg lorazepam. More studies with a larger number of subjects are warranted in which the short-term and (sub)long-term effects of benzodiazepines are investigated by combining indices of autonomic regulation (including total peripheral resistance and cardiac output) with detailed respiratory measurements further to clarify the potential differences between benzodiazepines. Because benzodiazepines are commonly prescribed as anxiolytics/hypnotics in patients with angina or a recent myocardial infarction, as well as in patients with anxiety and depressive disorders in which cardiovascular symptoms frequently occur, a differentiation among benzodiazepines regarding their autonomic effects, small as they may be, may prove to be beneficial for treatment strategies.
Acknowledgment: This study was supported by a grant from Upjohn-Nederland. We thank J.B.G.M. Noten (Pharmaceutical Department of the Vincent van Gogh Institute, Venray) for the assays of the plasma benzodiazepine concentrations and F. Boomsma (Department of Internal Medicine, Erasmus University, Rotterdam) for the assays of plasma catecholamine concentrations. F. van den Berg (Department of Psychiatry, Erasmus University, Rotterdam) assisted with the experiment.
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